Oops I “did” It Again: The Reformulation of didanosine
PHCY 512: Pharmaceutics and Drug Delivery Systems
February 15, 2016
Section 1 – Background Information
Many drug manufacturers target the stomach as to where a given drug will be absorbed.
The reason for this is that the stomach of the gastrointestinal tract has a pH of around 1.0
– 5.4 (depending on a number of various factors) (1). The problem that drug
manufacturers run into is that at such low pH levels, a drug will be absorbed in the
stomach as it goes through the GI tract even though that may not be the intended site of
absorption. So what drug manufacturers have done to alleviate this problem of “pre
mature absorption” is to coat their tablets with an enteric coat. An enteric coat is designed
to be absorbed in the basic environments of the small intestine (2). Enteric coating
consists of a sugar core that is engulfed by the active pharmaceutical ingredient (API).
Engulfing the API is then the enteric coating. The enteric coating is built to not dissolve
at low pHs, but will dissolve in higher pHs.
The drug Videx (generic name is didanosine) is a synthetic purine nucleoside analogue
active against the Human Immunodeficiency Virus (HIV) (3). Didanosine is unstable in
acidic solutions. For example, at pH <3 and 37° C, 10% of didanosine decomposes to
hypoxanthine in less than 2 minutes (3). Videx has many different formulations. It has a
pediatric powder for oral solution as well as an enteric-coated capsule formulation.
However, the drug company who produced this drug, Bristol- Myers Squibb didn’t
initially formulate this drug with an enteric coating. That is the case that will be
Section 2 – Primary Literature Summary
In this case, the drug company, Bristol-Myers Squibb originally did not want didanosine
to be absorbed in the stomach where the pH was so low. Therefore, they originally
decided to formulate their drug with antacids to prevent acid hydrolysis of the drug while
in the stomach (2). The only problem with this is that users of this formulation reported
side effects of diarrhea, nausea, and GI disturbances. This original formulation was in
tablet form, so Bristol- Myers Squibb decided to formulate an EC capsule to see if this
would reduce the GI side effects that were being experienced by their users. In February
of 2000, a six-week open label crossover study was conducted. Participants included
HIV-infected men and women (older than 18 years old) taking didanosine tablets either
once or twice daily, for four or more weeks (2). The participants were asked to rate how
severe symptoms of nausea, bloating, GI upset, diarrhea, abdominal cramps, and
flatulence were on a scale from 0-6 (6 being the most severe). They were to be placed on
the didanosine tablet for two weeks and then were to switch over to the didanosine EC
capsules for the remainder of the 6 weeks. After the six weeks, the severity scores were
lower across all of the six different symptoms. This can be seen in Figure 1. The striking
tolerability advantages appear to support routine switching to EC for such patients and
may suggest that widespread preferential selection of the EC form is appropriate to
enhance didanosine tolerability and promote treatment adherence (2). After the study was
completed, all 42 of the participants preferred the didanosine EC to the didanosine tablet.
Section 3 – Original Discussion
This case explicitly explains how pharmaceutics can play an instrumental role in
treatment efficacy for patients. The didanosine tablets probably had less adherence due to
all of the side effects that were associated with it. The decreased adherence long term
may cause physicians to prescribe a different drug that has fewer side effects. Negative
reviews from patients is probably what caused Bristol-Myers Squibb to go back and
continue to reformulate their drug.
Since there is some bacterial flora present in the ileum of the small intestines an
alternative solution could have been to attach polymers that can only be cleaved by those
bacteria (1). That would prevent absorption in the stomach, and will better aid in the
absorption in the small intestines. However, a problem with this alternative method is that
those polymers that are broken down by bacterial flora may have increased the overall
size of the didanosine formulation, or distort the taste making the drug less palatable.
Larger pills and a distorted taste could also decrease the adherence to specific
medications. Also, adding polymers that can be cleaved by bacteria is a feature that is
used more for absorption in the large intestines than the small intestines.
When critically evaluating the case, the didanosine EC formulation was clearly the better
choice. However, out of 42 individuals who completed the study, 45% had undetectable
HIV RNA. Also, the mean CD4 cell count was 506 cells. A healthy range is between
500-1200 cells (4). The use of antidiarrheal medications declined from 26 total doses in
week 2 (on tablets) to 11 doses in week 4 (on capsules) (2). This data could be misleading
because it is possible that since 45% of participants did not even have any detectable HIV
RNA, their cellular functions and body’s ability to function at a certain rate were working
more efficiently than the 55% who had detectable HIV RNA. Therefore, the decrease in
antidiarrheal medications decreased by a little less than half because half of the
participants had a healthier overall system. Also, the CD4 cell count is still within the
range of a healthy individual. A follow up study should be done where all of the
individuals have detectable HIV RNA as well as an overall lower mean CD4 cell count to
test if a decline in GI side effects is negligible in the later stages of HIV.
1. Jay M. Drug Formulation and Oral Dosage Form. Slide 4. Date accessed: February 14,
2. Kunches LM, Reinhalter NE, Marquis A, Coakley E, Cohen C, Morris AB, Mazzullo
JM. Tolerability of enteric coated didanosine capsules compared with didanosine tablets
in adults with HIV infection. J Acquir Immune Defic Syndr. 2001 Oct 1;28 (2):150-3.
PubMed PMID: 11588508.
3. Didanosine." (n.d.): n. pag. Videx Packet Insert. Bristol-Myers Squibb Company, Aug.
s39,20156s40,21183s16lbl.pdf. Accessed February 14, 2016.
4. CD4 Count." CD4 Count. AIDS.gov, 09 Sept. 2015. Web. <https://www.aids.gov/hiv-
Accessed February 14, 2016
Figure 1: Patients diary score for gastrointestinal symptoms on didanosine tablet or
didanosine EC capsule.
Taken from Kunches LM, Reinhalter NE, Marquis A, Coakley E, Cohen C, Morris
AB, Mazzullo JM. Tolerability of enteric-coated didanosine capsules compared with
didanosine tablets in adults with HIV infection. J Acquir Immune Defic Syndr. 2001
Oct 1;28(2):150-3. PubMed PMID: 11588508.